Hemoglobin is a vital iron-containing metalloprotein contained in red blood cells (RBCs). Hemoglobin transports oxygen from the lungs where it loads oxygen from alveolar gas to the tissues where it unloads oxygen. Allosteric effectors are small natural and synthetic molecules that bind to hemoglobin and shift the equilibrium between the oxygenated (R-state) and deoxygenated (T-state) states of hemoglobin by stabilizing the tertiary and quaternary conformations of hemoglobin. Shifting the equilibrium towards the R-state results in increased oxygen-binding affinity of hemoglobin and an increase of oxygenated hemoglobin within the red cell.
Aromatic aldehydes, isothiocyanates, aspirin derivatives, disulfides, and maleimides have been studied as allosteric effectors increasing the oxygen-binding affinity of hemoglobin. These molecules bind to hemoglobin, preferentially stabilizing the R-state, and shifting the allosteric equilibrium towards the R-state which has higher oxygen-binding affinity.
Allosteric effectors that increase the oxygen-binding affinity of hemoglobin may be used to treat sickle cell disease (SCD). SCD is an inherited disorder in which an abnormally mutated hemoglobin (HbS) causes red blood cells to sickle, thereby occluding small blood vessels. Sickled red blood cells can become leaky releasing toxic hemoglobin into the plasma. Sickled red blood cells are cleared from the circulation more rapidly than normal red blood cells leading to anemia. Under hypoxic conditions, deoxygenated HbS tetramers polymerize and distort the RBC into a sickled shape, causing occlusion and thrombosis of small blood vessels, thereby causing ischemia. Increasing the oxygen-binding affinity of sickle RBCs represents a therapeutic strategy for SCD because this increase of oxygen affinity can prevent release of oxygen and decreases the concentration of deoxygenated HbS that can polymerize causing sickling. Other uses of allosteric effectors which increase the oxygen affinity of hemoglobin is the prevention of high altitude tissue hypoxia. Increasing oxygen loading at the lung in extremely hypoxic high altitude exposures can increase survival and prevent systemic hypoxia (Eaton, J. W., Skelton, T. D. & Berger, E., “Survival at extreme altitude: protective effect of increased hemoglobin-oxygen affinity,” Science 183, 743-4 (1974)). This application addresses these needs and others.